Objectives: The aim of this project is to characterize an endogenous down-regulation of the calcium/calcineurin/NFAT signalling pathway that could lead to a strong inhibition of calcineurin activity after lymphocyte activation. Such an endogeneous down-regulation could consist in an activation of the synthesis of DSCR1, which is known to inhibit the activity of calcineurin, and/or in an inhibition of calcineurin synthesis.
– Main objective: To determine the protein expression of DSCR1 in the samples of the CALCILUNG library
– Secondary objectives: 1) To determine the protein expression of calcineurin in the samples of the CALCILUNG library, 2) To demonstrate, on a more fundamental level, that the activation of DSCR1 synthesis and/or the inhibition of calcineurin synthesis, constitute an endogenous down-regulation pathway of the calcium/calcineurin/NFAT signalling pathway after lymphocyte activation.
Methodology: This project combines a non-interventional biological study on the samples issued from the CALCILUNG library, and an in vitro study with primary cultures of human lymphocytes and Jurkat T-cells. The CALCILUNG study consisted in the monitoring of calcineurin activity for 24 months in 107 de novo lung-transplanted treated with cyclosporine.
Primary endpoint: Establishment of an inverse correlation between the expression of DSCR1 and the activity of calcineurin in the CALCILUNG study.
Secondary endpoints: 1) Establishment of a correlation between the protein expression of calcineurin and the activity of calcineurin in the CALCILUNG study, 2) establishment of an activation of the synthesis of inhibitors of calcineurin activity such as DSCR1 after in vitro lymphocyte activation, 3) establishment of an inhibition of calcineurin synthesis after in vitro lymphocyte activation.
Expected results : This study should 1) improve our academical knowledge of the interactions of CNIs with the calcium/calcineurin/NFAT signalling pathway in the context of graft rejection, 2) clarify the molecular mechanisms leading to an increased toxicity of CNIs, 3) develop new diagnostic tools to optimize the immunosuppressive therapy.